Methods and devices suitable for imaging blood-containing tissue

ABSTRACT

Disclosed are methods and devices useful for imaging blood-containing tissue, for example for angiography, especially retinal angiography, whereby an image is generated by dividing pixels of an image acquired at some wavelength range by corresponding pixels of an image acquired at a different wavelength range. In some embodiments, a first wavelength range includes predominantly light having wavelengths between about 400 nm and about 620 nm and a second wavelength range includes predominantly light having wavelengths between about 620 nm and about 800 nm.

RELATED APPLICATION

The present application gains priority from UK Patent Application GB1102209.2 filed 9 Feb. 2011.

FIELD AND BACKGROUND OF THE INVENTION

The invention, in some embodiments, relates to the field of medicalimaging, and more particularly but not exclusively, to methods anddevices suitable for imaging blood-containing tissue, for example forangiography, especially retinal angiography.

Angiography is a technique for the in vivo imaging of blood vessels.

In some instances, angiography is performed by administering aradio-opaque contrast agent in the blood vessels of a living subject andthen acquiring an image of the blood vessels using an X-ray imagingmodality. Such methods are useful, for example, to acquire a3-dimensional representation of cerebral blood vessels.

To avoid the use of an X-ray imaging modality, it is known to acquire avisible light image of shallow blood vessels in a bodily surface, forexample, in the retina or mucosa such as the gastrointestinal luminalwalls, with the use of fluorescence angiography. A fluorescent agent(e.g., sodium fluorescein or indocyanine green) is administered into theblood vessels of a subject. The surface to be imaged is illuminated witha fluorescence-exciting wavelength (e.g., 490 nm for sodium fluorescein,800 nm for indocyanine green) and a camera used to acquire an image fromthe light emitted by the fluorescent agent (e.g., 530 nm for sodiumfluorescein, 830 nm for indocyanine green).

It is also known to perform optical angiography, the use a suitablecamera to acquire a visible-light color image of blood vessels, thusavoiding the complexity, time and potential health hazards associatedwith the administration of a fluorescent agent.

Visible-light color images often have insufficient contrast to clearlydiscern smaller blood vessels. It has been found that “red-free” images(e.g., images acquired where the camera lens is functionally associatedwith a green filter to prevent red light from being gathered) havegreater contrast than color images.

In many fields, for example in the field of retinal angiography, itwould be useful to have improved performance for example, increasedcontrast and/or greater spatial resolution. Such improved performancemay allow gathering information useful in screening or diagnosingconditions such as cancer-related angiogenesis, diabetic retinopathy,age-related macular degeneration and cardiovascular and brain diseasesthat have been shown to be related to the morphology of the retinalmicrovasculature.

Some may consider U.S. Pat. Nos. 6,083,158; 6,104,939; 6,276,798;6,556,853 as well as US patent application 2007/0253033 and as providingbackground to some embodiments of the teachings herein.

SUMMARY OF THE INVENTION

Some embodiments of the invention relate to methods and devices suitablefor imaging blood-containing tissue, for example for performingangiography, that in some embodiments have advantages over known imagingmethods and devices.

Some embodiments of the methods and devices described herein an image isgenerated by dividing pixels of an image acquired at some wavelengthrange by corresponding pixels of an image acquired at a differentwavelength range. In some embodiments, a first wavelength range includespredominantly light having wavelengths between about 400 nm and about620 nm and a second wavelength range includes predominantly light havingwavelengths between about 620 nm and about 800 nm.

According to an aspect of some embodiments of the invention, there isprovided a method of generating an image of the surface of biologicaltissue, comprising:

-   -   a) acquiring a first pixelated image of an area of interest of        the surface at a first wavelength range of light, the first        wavelength range including predominantly light having        wavelengths of between about 400 nm and about 620 nm;    -   b) acquiring a second pixelated image of the area of interest of        the surface at a second wavelength range of light, the second        wavelength range including predominantly light having        wavelengths of between about 620 nm and about 800 nm;    -   c) generating a monochromatic third pixelated image from the        first image and the second image by:        -   for each desired location i of the area of interest,            identifying a corresponding pixel P1(i) in the first image            and a corresponding pixel P2(i) in the second image; and        -   calculating a pixel P3(i) in the third image corresponding            to the location i, by dividing one of P1(i) and P2(i) by the            other.

According to an aspect of some embodiments of the invention, there isalso provided a device useful for generating an image of the surface ofbiological tissue, comprising:

-   -   a) an image-acquirer suitable for acquiring a first pixelated        image of an area of interest of the surface of biological tissue        with a first wavelength range of light, the first wavelength        range including predominantly light having wavelengths of        between about 400 nm and about 620 nm;    -   b) an image-acquirer suitable for acquiring a second pixelated        image of the area of interest with a second wavelength range of        light, the second wavelength range including predominantly light        having wavelengths of between about 620 nm and about 800 nm; and    -   c) a processor configured to generate a monochromatic third        pixelated image from the first image and the second image by:        -   for each desired location i of an area of interest,            identifying a corresponding pixel P1(i) in the first image            and a corresponding pixel P2(i) in the second image; and        -   calculating a pixel P3(i) in the third image corresponding            to the location i, by dividing one of P1(i) and P2(i) by the            other.

As used herein, for clarity the term “image” refers to a visible image(e.g., as displayed on permanent media such as on printed paper orelectronic media such as a display screen (LED, LCD, CRT)), as well asdata (especially electronic data) representing the image including datastored, for example, on magnetic or electrical media (e.g., flashmemory, magnetic disk, magnetic tape).

As used herein, for clarity the term “pixel” refers to an element makingup a pixelated image (displayed or stored as data) and also to the valueof the pixel, as the context dictates.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention pertains. In case of conflict, thespecification, including definitions, will control.

As used herein, the terms “comprising”, “including”, “having” andgrammatical variants thereof are to be taken as specifying the statedfeatures, integers, steps or components but do not preclude the additionof one or more additional features, integers, steps, components orgroups thereof.

As used herein, the indefinite articles “a” and “an” mean “at least one”or “one or more” unless the context clearly dictates otherwise.

Embodiments of methods and/or devices described herein may involveperforming or completing selected tasks manually, automatically, or acombination thereof. Some methods and/or devices described herein areimplemented with the use of components that comprise hardware, software,firmware or combinations thereof. In some embodiments, some componentsare general-purpose components such as general purpose computers,digital processors or oscilloscopes. In some embodiments, somecomponents are dedicated or custom components such as circuits,integrated circuits or software.

For example, in some embodiments, some of an embodiment is implementedas a plurality of software instructions executed by a data processor,for example which is part of a general-purpose or custom computer. Insome embodiments, the data processor or computer comprises volatilememory for storing instructions and/or data and/or a non-volatilestorage, for example, a magnetic hard-disk and/or removable media, forstoring instructions and/or data. In some embodiments, implementationincludes a network connection. In some embodiments, implementationincludes a user interface, generally comprising one or more of inputdevices (e.g., allowing input of commands and/or parameters) and outputdevices (e.g., allowing reporting parameters of operation and results.

BRIEF DESCRIPTION OF THE FIGURES

Some embodiments of the invention are herein described with reference tothe accompanying figures. The description, together with the figures,makes apparent to a person having ordinary skill in the art how someembodiments of the invention may be practiced. The figures are for thepurpose of illustrative discussion and no attempt is made to showstructural details of an embodiment in more detail than is necessary fora fundamental understanding of the invention. For the sake of clarity,some objects depicted in the figures are not to scale.

In the Figures:

FIG. 1A is a reproduction of an image of the surface of the inner sideof a flap of abdominal skin of a mouse, with two regions marked: aregion including a blood vessel (a) and a region devoid of blood vessels(b);

FIG. 1B are the reflectance spectra of regions a and b in Figure lAbetween 400 nm and 800 nm;

FIG. 2A is a black-and-white reproduction of a standard RGB image of thesurface of the inner side of a flap of abdominal skin of a mouse;

FIG. 2B is a reproduction of a standard monochrome red-free narrow band(520 nm-580 nm) image of the surface of the inner side of a flap ofabdominal skin of a mouse;

FIG. 2C is a reproduction of an image of the surface of the inner sideof a flap of abdominal skin of a mouse generated in accordance with anembodiment of the method as described herein, where the first wavelengthrange was 400 nm to 600 nm and the second wavelength range was 600 nm to800 nm;

FIG. 3 is a schematic depiction of an embodiment of a fundus cameradevice as described herein suitable for implementing embodiments of themethod described herein including a single RGB multicolorimage-acquirer;

FIG. 4 is a schematic depiction of an embodiment of an ingestiblegastrointestinal imaging device as described herein suitable forimplementing embodiments of the method described herein including abeam-splitter, two wavelength filters and two monochromaticimage-acquirers;

FIG. 5 is a schematic depiction of an embodiment of a flexible endoscopedevice as described herein suitable for implementing embodiments of themethod described herein including a dichroic prism and two monochromaticimage-acquirers;

FIG. 6 is a schematic depiction of an embodiment of a rigid endoscopedevice as described herein suitable for implementing embodiments of themethod described herein including two light sources and a singlemonochromatic image-acquirer; and

FIG. 7 is a schematic depiction of an embodiment of a rigid endoscopedevice as described herein suitable for implementing embodiments of themethod described herein including two light sources and a singlemonochromatic image-acquirer; and

DESCRIPTION OF SOME EMBODIMENTS OF THE INVENTION

Some embodiments of the invention relate to methods and devices usefulfor imaging blood-containing tissue, for example for angiography,especially retinal angiography. In some embodiments, an image isgenerated by dividing pixels of an image acquired at some wavelengthrange by corresponding pixels of an image acquired at a differentwavelength range. In some embodiments, a first wavelength range includespredominantly light having wavelengths between about 400 nm and about620 nm and a second wavelength range includes predominantly light havingwavelengths between about 620 nm and about 800 nm.

The principles, uses and implementations of the teachings of theinvention may be better understood with reference to the accompanyingdescription and figures. Upon perusal of the description and figurespresent herein, one skilled in the art is able to implement theteachings of the invention without undue effort or experimentation. Inthe figures, like reference numerals refer to like parts throughout.

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not necessarily limited in itsapplication to the details of construction and the arrangement of thecomponents and/or methods set forth herein. The invention is capable ofother embodiments or of being practiced or carried out in various ways.The phraseology and terminology employed herein are for descriptivepurpose and should not be regarded as limiting.

Known methods for acquiring images of blood-containing tissue, such asin the field of angiography, have various shortcomings. Some methodsrequire administration of compositions into the body, for examplefluorescein or indocyanine compositions. Images acquired using knownmethods that do not include administration of such compositions areoften insufficiently clear.

In FIG. 1A an image of the surface of the inner side of a flap ofabdominal skin of a mouse is reproduced with two regions marked: aregion including a blood vessel (a) and a region devoid of blood vessels(b).

In FIG. 1B are depicted the reflectance spectra of region a (bloodvessel) and b (no blood vessel) between 400 nm and 800 nm as acquired bythe Inventor using a spectral imaging camera. It is seen that between620 nm and 800 nm, the reflectance of blood-containing tissue (a) andtissue substantially devoid of blood (b) is substantially the same. Itis also seen that between 400 nm and 620 nm, the reflectance ofblood-containing tissue (a) is significantly lower than that of thetissue substantially devoid of blood (b), attributable to the absorptionof light having such wavelengths by blood.

Herein are disclosed methods and devices useful for imagingblood-containing tissue, for example for angiography, especially retinalangiography. In some embodiments, an image is generated by dividingpixels of one image by corresponding pixels of another image, a firstimage acquired at a first wavelength range including predominantly lighthaving higher absorbance in blood than non-blood bodily tissue,generally having wavelengths of between about 400 nm and about 620 nmand a second image acquired at a second wavelength range includingpredominantly light having absorbance in blood similar to that ofnon-blood tissue generally having wavelengths of between about 620 nmand about 800 nm. It has been surprisingly found that in someembodiments, such a generated image has greater apparent detail due tohigher contrast and/or greater spatial detail when compared to imagesacquired using known methods.

In FIG. 2, three different pixelated images of the same surface of theinner side of a flap of abdominal skin of a mouse acquired and generatedby the Inventors using a spectral camera are depicted:

in FIG. 2A, a standard RGB image of the surface is reproduced in blackand white;

in FIG. 2B, a standard monochrome red-free narrow band (520 nm-580 nm)image of the surface is reproduced; and

in FIG. 2C, an image generated in accordance with an embodiment of themethod described herein (see Examples section) is reproduced where thefirst wavelength range was 400 nm to 600 nm and the second wavelengthrange was 620 nm to 800 nm.

Despite the relatively low quality of the reproductions in FIGS. 2A, 2Band 2C, it is seen that the teachings herein provide an image withgreater apparent detail.

It is seen that the image in FIG. 2C generated in accordance with theteachings herein has an unexpectedly superior contrast to the images inFIGS. 2A and 2B.

It is also seen that the image in FIG. 2C generated in accordance withthe teachings herein has an unexpectedly superior spatial resolution tothe images in FIGS. 2A and 2B. Although not wishing to be held to anyone theory, it is currently believed that in the known methods, thespatial resolution of the images is limited by the presence of photonsat specific wavelengths back-scattered by the tissue including tubularwalls of the blood vessels in the tissue. Apparently, the teachingsherein reduce the effect of such back-scattered photons so that theedges of the blood vessels in an image generated in accordance with theteachings herein are more clearly defined.

Whatever the reasons, the teachings herein have exceptional utility,allowing acquisition of high contrast and/or detailed images, in someembodiments in real time, of capillaries, arteries, veins, hemorrhagesand some blood-rich tumors. Images having greater spatial resolutionand/or greater contrast make automated diagnosis methods (e.g., methodsusing image processing or image-comparison techniques) more accurate.Images having greater spatial resolution and/or greater contrast providea health-care professional with more accurate information to diagnosesome pathologies such as bleeding, cancer-related angiogenesis (e.g.,retinal tumors such as melanoma), diabetic retinopathy, age-relatedmacular degeneration and cardiovascular and brain diseases.

Method for Generating an Image

According to an aspect of some embodiments of the teachings herein,there is provided a method suitable for generating an image of thesurface of biological tissue comprising:

-   -   a) acquiring a first pixelated image of an area of interest of        the surface at a first wavelength range of light, the first        wavelength range including predominantly light having        wavelengths of between about 400 nm and about 620 nm;    -   b) acquiring a second pixelated image of the area of interest of        the surface at a second wavelength range of light, the second        wavelength range including predominantly light having        wavelengths of between about 620 nm and about 800 nm;    -   c) generating a monochromatic third pixelated image from the        first image and the second image by:        -   for each desired location i of an area of interest,            identifying a corresponding pixel P1(i) in the first image            and a corresponding pixel P2(i) in the second image; and        -   calculating a pixel P3(i) in the third image corresponding            to the location i, by dividing one of P1(i) and P2(i) by the            other.

The biological surface is any suitable biological surface. In someembodiments, the biological surface is a biological surface selectedfrom the group consisting of a retina, skin, mucosa, gastrointestinalmucosa, oral mucosa, a gynecological tract surface, and a respiratorytract surface.

In some embodiments, the first image is a monochromatic image. In someembodiments, the second image is a monochromatic image.

In some embodiments, the third image has increased contrast betweenblood-containing features (such as blood vessels) and adjacent tissue,relative to comparable color or red-free images.

In some embodiments, the third image has increased spatial resolution atthe border between blood-containing features (such as blood vessels) andadjacent tissue, relative to comparable color or red-free images.

Typically but not necessarily, the first, second and third images allare of the same size (in terms of pixels) and are of the same area ofinterest of the surface. Consequently, during the generating of thethird image, all pairs of corresponding pixels from the first and secondimage are used together to calculate a corresponding pixel of the thirdimage.

In some embodiments, the first and second image are of the same size (interms of pixels) and are of the same area of interest of the surface butthe third image is smaller (e.g., of the same area of interest but fewerpixels to have lower resolution, or of a smaller area of interest havingthe same or lower resolution). In such embodiments, the pixelsconstituting the third image are calculated from the corresponding pairsof pixels from the first and second image.

In some embodiments, one of the first and second image is smaller thanthe other (in terms of pixels) and/or in terms of the area of interestof the surface. In some such embodiments, the third image is of the samesize as the smaller of the first and second images. In some suchembodiments, the third image is smaller and/or of a smaller area ofinterest. In such embodiments, the pixels constituting the third imageare calculated from the corresponding pairs of pixels from the first andsecond image.

In some embodiments, the method further comprises storing the thirdimage, for example on a flash memory (e.g., SD card) or magnetic memory(e.g., hard disk) data storage component. In some embodiments, themethod further comprises displaying the third image in a manner visibleto a person, for example on a display screen (e.g., LED, LCD or CRTdisplay screen) or on permanent media (printed on paper of film). Insome embodiments, the displaying is in real time.

In some embodiments, the third image undergoes post-processing prior tostoring and/or displaying. Typical post-processing includes, but is notlimited to, cropping, rotation, resizing and changes in color depth.

In some embodiments, prior to the generating of the third image, thepixels of the first image, of the second image or of both the first andthe second image are normalized relative to some specific wavelength,for example for intensity balancing.

In some embodiments, a mathematical formula describing the calculatingof a pixel of the third image from the two corresponding pixels of thefirst and second images is substantially a mathematical formula selectedfrom the group consisting of:

P3(i)=[(xP1(i)+m)^(A)/(yP2(i)30 n)^(B)] andP3(i)=[(yP2(i)+n)^(B)/(xP1(i)+m)^(A)],

wherein A and B are, independently, any suitable (preferably real)positive number except 0 and including 1; and

-   wherein x and y are, independently, any suitable (preferably real)    number including 1; and-   wherein m and n are, independently, any suitable (preferably real)    number including 0.

In some embodiments, the mathematical formula is substantially amathematical formula selected from the group consisting ofP3(i)=[P1(i)/P2(i)] and P3(i)=[P2(i)/P3(i)].

In some embodiments, the method further comprises illuminating the areaof interest with light comprising wavelengths within the firstwavelength range during the acquiring of the first pixelated image; andilluminating the area of interest with light comprising wavelengthswithin the second wavelength range during the acquiring of the secondpixelated image. In some embodiments, the illuminating is withincoherent light. In some embodiments, the illuminating is withpolarized light. In some embodiments, the illuminating with lightcomprising wavelengths within the first wavelength range is simultaneouswith the illuminating with light comprising wavelengths within thesecond wavelength range. In some such embodiments, the illuminating iswith white light (e.g., a light-emitting diode emitting white light, awhite-light lamp). In some such embodiments, the illuminating is withlight having at least two discrete wavelengths of light: at least onediscrete wavelength within the first wavelength range (e.g., with alight-emitting diode emitting yellow, green or blue light) and at leastone discrete wavelength within the second wavelength range (e.g., with alight-emitting diode emitting red light).

In some embodiments, the acquiring of the first pixelated image is notsimultaneous with the acquiring of the second pixelated image, and themethod further comprises:

-   -   illuminating the area of interest with light comprising        wavelengths within the first wavelength range (e.g., with a        light-emitting diode emitting yellow, green or blue light)        during the acquiring of the first pixelated image; and    -   illuminating the area of interest with light comprising        wavelengths within the second wavelength range (e.g., with a        light-emitting diode emitting red light) during the acquiring of        the second pixelated image.

In some such embodiments, during the acquiring of the first pixelatedimage, illuminating the area of interest is with light substantiallydevoid of wavelengths within the second wavelength range. In some suchembodiments, during the acquiring of the second pixelated image,illuminating the area of interest is with light substantially devoid ofwavelengths within the first wavelength range.

Generally, the first image and the second image are acquired using oneor more pixelated image-acquirers as known in the field of digitalphotography, e.g., CCD arrays and CMOS arrays that typically use one ormore arrays of light-sensitive sensors to acquire an image from lightgathered by an objective.

In some embodiments, the first image and the second image are acquiredsubstantially simultaneously.

For example, in some such embodiments the method comprises:

-   -   directing light collected for acquiring the first image from the        area of interest to a first image-acquirer to acquire the first        image; and    -   directing light collected for acquiring the second image from        the area of interest to a second image-acquirer different from        the first image-acquirer to acquire the second image.

In some embodiments, such directing of light is achieved using opticalelements such as one or more of light filters, polarization filters,beam splitters, dichroic and trichroic prisms that direct the differentwavelengths of light to the different image-acquirers.

For example, in some such embodiments the method comprises:

-   -   directing light collected for acquiring the first image and the        second image from the area of interest to a single        image-acquirer;    -   separating data acquired by the single image-acquirer        constituting the first image from data acquired by the single        image-acquirer constituting the second image.

In some embodiments, such separating of data is performed by usingdifferent color outputs of a single-image-acquirer to generate the firstand the second image. For example, in some such embodiments, animage-acquirer is a Foveon-X3 CMOS image-acquirer (NationalSemiconductor, Santa Clara, Calif., USA) that has separate outputs forblue, green and red pixels. For example, in some such embodiments, animage-acquirer is a CCD or CMOS image-acquirer including a Bayer orother wavelength filter that has separate outputs for red, green andblue pixels (RGB), or other wavelength filters such as red, green, blue,emerald pixels (RGBE filter), red, green, blue and white pixels (RGBW)and cyan, magenta, yellow and white pixels (CMYW).

In some embodiments, cross-polarization filters are used forillumination light and for collected light, which in some embodimentsreduces or eliminates some of the negative effects of specularreflections.

In some embodiments, the first and second image are acquiredsequentially. To overcome the possibility that the area of interestmoved in the frame of the images between acquisition of the first andsecond images, stitching algorithms (such as known in the field ofdigital photography) are typically used to match a pixel from the firstimage and a corresponding pixel from the second image to calculate acorresponding pixel of the third image.

In some such embodiments, a device includes a single multicolorimage-acquirer. In some such embodiments, a device includes a singlemonochrome image-acquirer.

For example, in some such embodiments, the image-acquirer isfunctionally associated with a changing (e.g., rotating) wavelengthfilter that changes from a first state (that allows light from the firstwavelength range to reach the image-acquirer) to a second state (thatallows light from the second wavelength range to reach theimage-acquirer). When the wavelength filter is in a first state,predominantly (in some embodiments only) light from the first wavelengthrange of light reaches the image-acquirer and the first image isacquired. When the wavelength filter is in a second state, predominantly(in some embodiments, only) light from the second wavelength range oflight reaches the image-acquirer and the second image is acquired.

For example, in some such embodiments, the area of interest isalternately illuminated with light having different wavelengths. Whenthe area of interest is illuminated predominantly with light having thefirst wavelength range of light,the first image is acquired. When thearea of interest is illuminated predominantly with light having thesecond wavelength range the second image is acquired.

In any given embodiment, the first image is acquired at a firstwavelength range of light, that predominantly includes light havingwavelengths of between about 400 nm and about 620 nm and the secondimage is acquired at a second wavelength range of light, thatpredominantly includes light having wavelengths of between about 620 nmand about 800.

In some embodiments, the first image is acquired at a first wavelengthrange of light, that exclusively includes light having wavelengths ofbetween about 400 nm and about 620 nm: it is currently believed that insome instances such embodiments provide the greatest improvement inimage-quality.

That said, in some embodiments the first image is acquired with somelight having wavelengths of between about 620 nm and about 800. In suchembodiments, the first wavelength range and the second wavelength rangeare together chosen to achieve the desired improvement in image-quality.

In some embodiments, the second image is acquired at a second wavelengthrange of light, that exclusively includes light having wavelengths ofbetween about 620 nm and about 800 nm: it is currently believed that insome instances such embodiments provide the greatest improvement inimage-quality.

That said, in some embodiments the second image is acquired with somelight having wavelengths of between about 400 nm and about 620. Forexample, the second image used in generating the image reproduced inFIG. 2C included light having wavelengths of about 600 nm and 800 nm. Insuch embodiments, the first wavelength range and the second wavelengthrange are together chosen to achieve the desired improvement in imagequality. For example, in some embodiments, the first image is acquiredat a first wavelength range of light, that exclusively includes lighthaving wavelengths of between about 400 nm and about 620 nm (e.g., alllight having a wavelength from 400 nm to 620 nm, or light having awavelength from about 400 nm to about 600 nm) and the second image isacquired at a second wavelength range of light, that includes lighthaving wavelengths of between about 400 nm and about 800 nm.

In some embodiments, the first wavelength range is centered between alower wavelength of about 400 nm (in some embodiments, between about 400nm and about 450 nm) and an upper wavelength of about 620 nm (in someembodiments between about 550 nm and about 620 nm). In some embodiments,the first wavelength range is centered between a lower wavelength ofabout 450 nm and an upper wavelength of about 580 nm. In someembodiments, the first wavelength range is centered between a lowerwavelength of about 480 nm and an upper wavelength of about 550 nm.

In some embodiments, the first wavelength range has a narrow bandwidth:e.g., having a bandwidth of less than about 5 nm, less than about 3 nmand even less than about 2 nm.

In some embodiments, the first wavelength range has a wide bandwidth,allowing more light to be gathered to acquire the first image with theconcomitant high signal to noise ratio. In some such embodiments, thefirst wavelength range has a bandwidth of at least about 5 nm, at leastabout 10 nm, at least about 20 nm, at least about 40 nm and even atleast about 80 nm.

In some embodiments, the first wavelength range is centered between alower wavelength of about 620 nm (in some embodiments, between about 620nm and about 650 nm) and an upper wavelength of about 800 nm (in someembodiments between about 700 nm and about 800 nm). In some embodiments,the second wavelength range is centered between a lower wavelength ofabout 620 nm and an upper wavelength of about 700 nm. In someembodiments, the second wavelength range is centered between a lowerwavelength of about 620 nm and an upper wavelength of about 650 nm.

In some embodiments, the second wavelength range has a narrow bandwidth:e.g., having a bandwidth of less than about 5 nm, less than about 3 nmand even less than about 2 nm.

In some embodiments, the second wavelength range has a wide bandwidth,allowing more light to be gathered to acquire the second image with theconcomitant high signal to noise ratio. In some such embodiments, thesecond wavelength range has a bandwidth of at least about 5 nm, at leastabout 10 nm, at least about 20 nm, at least about 40 nm and even atleast about 80 nm.

Embodiments of the method may be implemented using any suitable device.For example, the first and second pixelated images may be acquired usinga standard camera (with required modification,. That said, in someembodiments it is preferable to use a device as described herein.

Device for Generating an Image

According to an aspect of some embodiments of the teachings herein,there is provided a device suitable for generating an image of thesurface of biological tissue comprising:

-   -   a) an image-acquirer suitable for acquiring a first pixelated        image of an area of interest of the surface of biological tissue        with a first wavelength range of light, the first wavelength        range including predominantly light having wavelengths of        between about 400 nm and about 620 nm;    -   b) an image-acquirer suitable for acquiring a second pixelated        image of the area of interest of the surface of biological        tissue with a second wavelength range of light, the second        wavelength range including predominantly light having        wavelengths of between about 620 nm and about 800 nm;    -   c) a processor configured to generate (in some embodiments,        automatically) a monochromatic third pixelated image from the        first image and the second image by:        -   for each desired location i of an area of interest,            identifying a corresponding pixel P 1(i) in the first image            and a corresponding pixel P2(i) in the second image; and        -   calculating a pixel P3(i) in the third image corresponding            to the location i, by dividing one of P1(i) and P2(i) by the            other.

The device is any suitable device. In some embodiments, the device is adevice selected from the group consisting of a medical camera, aningestible endoscope, an endoscope, an ophthalmoscope and a funduscamera.

The first wavelength range is any suitable wavelength range, asdescribed above. The second wavelength range is any suitable wavelengthrange, as described above.

The calculating is performed substantially as described above.

In some embodiments, the device further comprises an illuminatorconfigured: to illuminate an area of interest with light comprisingwavelengths within the first wavelength range during acquisition of afirst pixelated image; and to illuminate an area of interest with lightcomprising wavelengths within the second wavelength range duringacquisition of a second pixelated image. In some embodiments, theillumination light is incoherent light. In some embodiments, theillumination light is polarized light.

In some embodiments, the illuminator is configured to simultaneouslyilluminate an area of interest with light comprising wavelengths withinthe first wavelength range and wavelengths within the second wavelengthrange. In some such embodiments. the illuminator includes a source ofwhite light. In some such embodiments, the illuminator includes a sourceof at least two discrete wavelengths of light, at least one discretewavelength of light within the first wavelength range and at least onediscrete wavelength of light within the second wavelength range.

In some embodiments, the illuminator includes a source of at least twodiscrete wavelengths of light, at least one discrete wavelength of lightwithin the first wavelength range and at least one discrete wavelengthof light within the second wavelength range, and the device isconfigured:

-   -   to illuminate an area of interest with a discrete wavelength of        light within the first wavelength range only during acquisition        of first pixelated image; and    -   to illuminate an area of interest with a discrete wavelength of        light within the second wavelength range only during acquisition        of second pixelated image.

In some embodiments, the image-acquirer suitable for acquiring the firstpixelated image and the image-acquirer suitable for acquiring the secondpixelated image are the same image-acquirer, generally a multicolorimage-acquirer.

In some embodiments, the image-acquirer suitable for acquiring the firstpixelated image and the image-acquirer suitable for acquiring the secondpixelated image are different image-acquirers, in some embodimentsmonochrome image-acquirers and in some embodiments multicolorimage-acquirers. In some embodiments, the device further comprises atleast one optical element to direct light of the first wavelength rangeto the first-image acquirer and light of the second wavelength range tothe second-image acquirer.

In some embodiments, the device is configured to acquire the first imageand the second image substantially simultaneously.

In some such embodiments, the device comprises an optical element thatdirects light gathered by an objective to different image-acquirers(monochrome or multicolor), at least one image-acquirer configured toacquire the first image and at least one image-acquirer configured toacquire the second image. In some such embodiments, the optical elementis, for example, a dichroic prism or a trichroic prism that directslight from the first wavelength range to the first-image acquirer oracquirers and directs light from the second wavelength range to thesecond-image acquirer or acquirers. In some such embodiments, theoptical element is, for example, a beam splitter, that directs somelight to the first-image acquirer or acquirers through a wavelengthfilter that allows only light of the first wavelength range to pass anddirects some light to the second-image acquirer or acquirers through awavelength filter that allows only light of the second wavelength rangeto pass.

In some such embodiments, the device comprises a single multicolorimage-acquirer configured to acquire both the first and the secondimage, In some such embodiments, the multicolor image-acquirer hasseparate outputs for each color, for example a Foveon-X3 CMOSimage-acquirer that has separate outputs for blue, green and red pixelsor a CCD or CMOS image-acquirer including a Bayer or other wavelengthfilter that has separate outputs for red, green and blue pixels (RGB),or other wavelength filters such as red, green, blue, emerald pixels(RGBE filter).

In some embodiments, the device is configured to acquire the first imageand the second image sequentially. In some such embodiments, the devicecomprises a single image-acquirer, in some embodiments a multicolorimage-acquirer, in some embodiments a monochrome image-acquirer. In someembodiments, the image-acquirer is functionally associated with achanging (e.g., rotating) wavelength filter that changes from a firststate (that allows light from the first wavelength range to reach theimage-acquirer) to a second state (that allows light from the secondwavelength range to reach the image-acquirer). When the wavelengthfilter is in a first state, the device is configured to acquire a firstimage as only light from the first wavelength range of light reaches theimage-acquirer and the first image is acquired. When the wavelengthfilter is in a second position, the device is configured to acquire asecond image as only light from the second wavelength range of lightreaches the image-acquirer and the second image is acquired.

In some embodiments, the device includes an illuminator configured toalternately illuminate an area of interest with light having differentwavelengths. The device is configured to acquire a first image when anarea of interest is illuminated with light of the first wavelength rangeof light and to acquire a second image when the area of interest isilluminated with light of the second wavelength range of light.

In some embodiments, the device is configured to store an acquired firstimage and an acquired second image. In some embodiments, the device isconfigured to store the third image.

In some embodiments, the device further comprises a display componentconfigured to visually display a generated third image. In someembodiments, the device further comprises a display component configuredto automatically visually display a generated third image. In someembodiments, the device further comprises a display component configuredto visually display a generated third image upon receipt of command froma user.

In some embodiments, the device further comprises an illuminatorconfigured to illuminate an area of interest with light comprising boththe first wavelength range and the second wavelength range. In someembodiments, the illumination with the first wavelength range issimultaneous with illumination with the second wavelength range. In someembodiments, the illumination with the first wavelength range isseparate from the illumination with the second wavelength range. In someembodiments, the light is incoherent light. In some embodiments, theilluminator is configured to illuminate the area of interest with whitelight. In some embodiments, the light source is configured to illuminatethe surface of biological tissue with either light of the firstwavelength range or light of the second wavelength range at any onetime.

An embodiment of a device useful for generating an image of the surfaceof biological tissue, specifically a fundus camera 10 for generating animage of a retina, is schematically depicted in FIG. 3.

Device 10 is similar to known fundus cameras. Device 10 comprises anilluminator 12, configured to illuminate an area of interest of a retinawith white incoherent light including substantially all wavelengths oflight from 400 to 800 nm. Device 10 also comprises an objective 14, togather light reflected from a retina and focus the light onto thelight-detecting surface of a single multicolor image-acquirer 16, a12-megapixel CMOS RGB detector array with a Bayer filter, havingseparate red pixels output 18, green pixels output 20 and blue pixeloutput 22. A processor 24 is configured to receive outputs 18, 20 and 22and to generate a third image from the outputs in accordance with theteachings herein. Processor 24 is functionally associated with a memory26 (an SDHC flash memory) to store acquired images and generated images.Processor 24 is also functionally associated with a display screen 28, aLED display screen.

For use, the chin of a subject is rested on chin-rest 29 so that the eyeof a subject is appropriately positioned relative to objective 14.Illuminator 12, image-acquirer 16 and processor 24 are activated. Lightfrom illuminator 12 is reflected from the area of interest of the retinaand focused onto the light-detecting surface of image-acquirer 16 whichsimultaneously acquires data corresponding to three monochromatic imagesthat are separately directed to processor 24: a red image through redpixel output 18, a green image through green pixel output 20 and a blueimage through blue pixel output 22. Processor 24 stores the threeacquired images in memory 26.

Depending on the user instructions (that can be changed through adevice-user interface, not depicted), processor 24 generates an imagefrom at least two of the acquired images, stores the generated image inmemory 26 and automatically displays the generated image on displayscreen 28 in real time.

The user can instruct processor 26 to generate a third image asdescribed above from:

the green image as a first image and the red image as a second image;

the blue image as a first image and the red image as a second image; or

a combination (e.g., sum or weighted sum) of the blue and green imagesas a first image and the red image as a second image.

Image-acquirer 16 of device 10 is a CMOS (complementary metal oxide) RGBdetector array with a Bayer filter, having separate red pixels output18, green pixels output 20 and blue pixel output 22. In some relatedembodiments an image-acquirer is another detector technology, forexample, a CCD (charge-coupled device) array, a PD (photodiode) array,or a LED (light-emitting diode) array. In some related embodiments, theimage-acquirer is RGB but with a filter different from a Bayer filter(e.g., a filter similar to the filter used in a S9706 color sensor byHamamatsu Photonics K.K. (Hamamatsu, Japan)) or a Foveon-X3 CMOSimage-acquirer.

In some related embodiments, an image-acquirer has other colors. Forexample, in some embodiments the image-acquirer is an RGBEimage-acquirer with four separate outputs: a red pixel output foracquiring a red image, a green pixel output for acquiring a green image,a blue pixel output for acquiring a blue image and an emerald pixeloutput for acquiring an emerald image. In some such embodiments, any ofthe green, blue and emerald images, singly or in combination of two orcombination of three can be used a first image as described herein whilethe red image is used as a second image.

It is important to note that often the spectral response of a multicolorimage-acquirer to a specific color is far from monochromatic. Forexample, the red of a typical Bayer filter has a peak sensitivity tolight having wavelengths of 610 to 630 nm, that is gradually reducedtowards 800 nm and is sharply reduced, but still significant down to 570nm. Consequently, in some embodiments a second image such as a red imagein the embodiment described above, includes wavelengths outside therange of 620 nm to 800 nm.

An additional embodiment of a device useful for generating an image ofthe surface of biological tissue, specifically an ingestible device 30for gastrointestinal imaging is schematically depicted in FIG. 4.

Device 30 is similar to known ingestible devices for gastrointestinalimaging such as the Pillcam™ (Given Imaging, Yokneam, Israel). Device 30comprises an illuminator 12, configured to illuminate an area ofinterest of intestinal mucosa with white incoherent light includingsubstantially all wavelengths of light from 400 to 800 nm. Device 30also comprises an objective 14, to gather light reflected from theintestinal mucosa of a gastrointestinal tract in which device 30 isfound and focus the light towards a beam-splitter 32, a half-silveredmirror, that directs light from objective 14 in two directions: in afirst direction 34 a through a first wavelength filter 36 a (configuredto pass light having a wavelength less than 620 nm and to block lighthaving a wavelength greater than 620 nm) to impinge on thelight-sensitive surface of a first image-acquirer 38 a, a 12 megapixelmonochrome CCD detector array and in a second direction 34 b through asecond wavelength filter 36 b (configured to pass light having awavelength greater than 620 nm and to block light having a wavelengthless than 620 nm) to impinge on the light-sensitive surface of a secondimage-acquirer 38 b, a 12 megapixel monochrome CCD detector array.Suitable wavelength filters are available, for example, from LeeFilters, Andover, Hampshire, England.

A processor 24 is configured to periodically receive acquired imagesfrom first image-acquirer 38 a and second image-acquirer 38 b, and togenerate a third image from the images in accordance with the teachingsherein. As known in the art of ingestible gastrointestinal imagingdevices, processor 24 is functionally associated with a wirelessBluetooth® transmitter 40 that transmits acquired images and generatedimages to an external unit (not depicted). The various components ofdevice 30 receive electrical power required for operation from powersource 42, a lithium ion battery.

For use, device 30 is activated and ingested by a subject. Illuminator12, image-acquirers 38 a and 38 b, processor 24 and transmitter 40 areactivated. As device 30 is propelled through the gastrointestinal tractof the subject, light from illuminator 12 is reflected from areas ofinterest of the intestinal mucosa retina and directed by objective 14and beam-splitter 32 in first direction 34 a and second direction 34 b.Light traveling in first direction 34 a passes through first wavelengthfilter 36 a to the light sensitive surface of first image-acquirer 38 a,that acquires a first image from the light. Light traveling in seconddirection 34 b passes through second wavelength filter 36 b to the lightsensitive surface of second image-acquirer 38 b, that acquires a secondimage from the light. Processor 24 receives the acquired first andsecond images from the respective image-acquirers 38 and generates athird image from the first and second images substantially as describedabove. Processor 24 then transmits the acquired images and the generatedimage to an external unit using transmitter 40.

In embodiments related to device 30, the device transmits acquired firstimages and second images to an external unit, and the external unit isconfigured to generate a third image from the acquired first and secondimages.

In some embodiments related to device 30, illuminator 12 comprises awhite-light illumination source, such as a white-light emitting LED, toprovide simultaneous illumination with light having wavelengths in boththe first and second wavelength range.

In some embodiments related to device 30, illuminator 12 comprises atleast two discrete light sources (e.g., colored-light emitting LEDs) toprovide simultaneous illumination with light having wavelengths in boththe first (e.g., 420 nm or 560 nm) and the second wavelength range(e.g., 620 nm).

An additional embodiment of a device useful for generating an image ofthe surface of biological tissue, specifically a flexible endoscope 44for imaging the inner surfaces of bodily hollows is schematicallydepicted in FIG. 5. Device 44 comprises a flexible shaft 46 having adistal end 48 schematically depicted in detail in FIG. 5. Not depictedin FIG. 5 is the bulk of shaft 46, the proximal end of device 44, aswell as other components such as steering components well known in theart of endoscopy.

Device 44 is similar to known flexible endoscopes. Device 44 comprisesan illuminator 12, configured to illuminate an area of interest of asurface of a bodily hollow with white incoherent light includingsubstantially all wavelengths of light from 400 to 800 nm. Device 44also comprises an objective 14, to gather light reflected from the areaof interest at which illuminator 12 is directed and focus the lighttowards a dichroic prism 50, that directs light from objective 14 in twodirections: light having a wavelength of less than 600 nm is directed ina first direction 34 a to impinge on the light-sensitive surface of afirst image-acquirer 38 a, a 12 megapixel monochrome CCD detector arraywhile light having a wavelength of greater than 600 nm is directed in asecond direction 34 b to impinge on the light-sensitive surface of asecond image-acquirer 38 b, a 12 megapixel monochrome CCD detectorarray. Suitable dichroic prisms are available, for example, from Optec,Parabiago, Milano, Italy.

A processor 24 is configured to periodically receive acquired imagesfrom first image-acquirer 38 a and second image-acquirer 38 b, and togenerate a third image from the images in accordance with the teachingsherein. Processor 24 transmits acquired images for storage and generatedimages for storage and display to an external unit (not depicted)through communication cable 52 that passes through shaft 46 to thedistal end of device 44. The various components of device 44 receiveelectrical power required for operation through lead 54.

For use, device 44 is activated and inserted into a hollow of a subjectas known in the art. Illuminator 12, image-acquirers 38 a and 38 b andprocessor 24 are activated. As device 44 is steered inside the hollow,light from illuminator 12 is reflected from areas of interest of theinner surface of the hollow and directed by objective 14 and dichroicprism 50 in first direction 34 a and second direction 34 b. Lighttraveling in first direction 34 a reaches the light sensitive surface offirst image-acquirer 38 a, that acquires a first image from the light.Light traveling in second direction 34 b reaches the light sensitivesurface of second image-acquirer 38 b, that acquires a second image fromthe light. Processor 24 receives the acquired first and second imagesfrom the respective image-acquirers 38 and generates a third image fromthe first and second images substantially as described above. Processor24 then transmits the acquired images and the generated image to anexternal unit through communication cable 52.

In embodiments related to device 30, the device transmits acquired firstimages and second images to an external unit, and the external unit isconfigured to generate a third image from the acquired first and secondimages. The generated image is displayed in real time, on a displaydevice.

It is important to note that depending on the exact embodiment, device44 is substantially any suitable type of flexible endoscope including,but not limited to, an esophagogastroduodenoscope, an enteroscope, acholangiopancreatoscope, a colonoscope, a sigmoidoscope, a rhinoscope, abronchoscope, a cystoscope, a gynoscope, a hysteroscope, a falloposcope,an amnioscope, a gastroscope, an otoscope, a laparoscope, a panendoscopeor a fetoscope.

In device 44, the image-acquiring components are found at distal end 48of device 44. In some embodiments, the image-acquiring components arefound at the proximal end of the device and light from an area ofinterest on a surface of tissue is directed through a light guide (e.g.,an optical fiber) passing from distal end 48 through flexible shaft 46to the proximal end.

In a related non-depicted embodiment, a device as described hereinincludes a trichroic prism (or even an n-chroic prism, where n isgreater than 3) instead of a dichroic prism to direct differentwavelength ranges of light from objective 14 in different directions. Atleast two different wavelength ranges, in some embodiments more, aredirected each to a different image-acquirer to acquire an image. A firstimage and a second image, as described hereinabove, are acquired andused to generate a third image in accordance with the teachings herein.

An additional embodiment of a device useful for generating an image ofthe surface of biological tissue, specifically a rigid endoscope 56(e.g., suitable for use as a laparoscope during keyhole surgery) forimaging the inner surfaces of bodily hollows is schematically depictedin FIG. 6. Device 56 comprises a rigid shaft 58 having a proximal end 60schematically depicted in FIG. 6. Not depicted in FIG. 6 is the bulk ofshaft 58, the distal end of device 56, as well as other components wellknown in the art of endoscopy.

Device 56 is similar to known rigid endoscopes. Device 56 comprises anilluminator 12. Illuminator 12 includes a white incoherent light sourcethat is functionally associated with a changeable wavelength filter 62having two states (determined, for example, by a rotating disk bearingtwo different wavelength filters). In a first state, light having awavelength of less than 620 nm passes through changeable wavelengthfilter 62 into an illumination channel 64 that passes through shaft 58to emerge through the distal tip of shaft 58 to illuminate an area ofinterest of a surface of bodily tissue, while light having a wavelengthgreater than 620 nm is blocked by changeable wavelength filter 62. In asecond state, light having a wavelength of greater than 620 nm passesthrough changeable wavelength filter 62 into an illumination channel 64that passes through shaft 58 to emerge through the distal tip of shaft58 to illuminate an area of interest of a surface of bodily tissue,while light having a wavelength less than 620 nm is blocked bychangeable wavelength filter 62. A processor 24 is configured to controlthe state of changeable wavelength filter 62

Passing from the distal tip of shaft 58 is a light guide 66 (an opticalfiber as known in the art of endoscopy) that directs light from thedistal tip of shaft 58 to an objective 14. Objective 14 focuses lightgathered from the distal tip of shaft 58 at the light-sensitive surfaceof an image-acquirer 38, a 12 megapixel multicolor (in some relatedembodiments, monochrome) CCD detector array.

Processor 24 is configured to repeatedly accept an image acquired byimage-acquirer 38 when changeable wavelength filter 62 is in the firststate as a first acquired image, then change the state of changeablewavelength filter 62 to the second state and accept an image acquired byimage-acquirer 38 when changeable wavelength filter 62 is in the secondstate as a second acquired image. Thus, device 56 is configured toacquire the first image and the second image sequentially.

Using an algorithm based on standard stitching algorithms known in theart of digital photography, processor 24 is configured to identifycorresponding pixels of an acquired first image and a succeeding orpreceding acquired second image, and generate a third image from pairsof corresponding pixels from acquired first and second images inaccordance with the teachings herein. Processor 24 transmits acquiredimages for storage and generated images for storage and display to anexternal unit (not depicted) through communication cable 52.

For use, device 56 is activated and inserted into a hollow of a subjectas known in the art, e.g., through a surgical port. Illuminator 12,image-acquirer 38 and processor 24 are activated. The distal end ofdevice 56 is directed at a surface so that light from illuminator 12passes through illumination channel 64 towards an area of interest, andis reflected. Reflected light is directed through light guide 66 toobjective 14. Objective 14 directs the light to the light sensitivesurface of image-acquirer 38, that alternately acquires a first imageand a second image depending on the state of changeable wavelengthfilter 62, as described above. Processor 24 receives the acquired firstand second images from image-acquirer 38 and generates a third imagefrom the first and second images substantially as described above.Processor 24 then transmits a generated image to be displayed on adisplay unit in real time.

In some embodiments described above, an illuminator configured toproduce white light is used to illuminate an area of interest. In somealternate embodiments, a device includes an illuminator configured toproduce a limited number of wavelengths of light to illuminate an areaof interest. In such embodiments, at least one wavelength is betweenabout 400 nm and about 620 nm (preferably between 475 nm and 560 nmwhere the difference in reflectance between blood and no blood is mostpronounced) and at least one wavelength is between about 620 nm andabout 800 nm (preferably between about 620 nm and 675 nm where theintensity of reflectance is highest). Typically, such an illuminatorincludes two separate light sources such as two monochromatic LEDs

An additional embodiment of a device useful for generating an image ofthe surface of biological tissue, specifically a rigid endoscope 68(e.g., suitable for use as a laparoscope during keyhole surgery) forimaging the inner surfaces of bodily hollows is schematically depictedin FIG. 7.

Like device 56, device 68 is similar to known rigid endoscopescomprising a rigid shaft 58 having a proximal end 60. Device 68comprises an illuminator 12 including two independently activatablesubstantially-monochromatic incoherent light sources, light-emittingdiode 70 a (green LED emitting light at 500 nm) and light-emitting diode70 b (red LED emitting light at 630 nm). When one or both LEDs 70 a or70 b are activated, the emitted light passes into and through anillumination channel 64 that passes through shaft 58 to emerge throughthe distal tip of shaft 58 to illuminate an area of interest of asurface of bodily tissue.

Like in device 56, passing from the distal tip of shaft 58 is a lightguide 66 that directs light from the distal tip of shaft 58 to anobjective 14. Objective 14 focuses light gathered from the distal tip ofshaft 58 at the light-sensitive surface of an image-acquirer 38, a 12megapixel multicolor (in some related embodiments, monochrome) CCDdetector array.

Processor 24 is configured to repeatedly activate LED 70 a to illuminatean area of interest with monochromatic light having a wavelength of 500nm and accept an image acquired by image-acquirer 38 as a first acquiredimage, and then to activate LED 70 b to illuminate an area of interestwith monochromatic light having a wavelength of 630 nm and accept animage acquired by image-acquirer 38 as a second acquired image. Thus,device 68 is configured to acquire the first image and the second imagesequentially.

Like in device 56, processor 24 of device 68 is configured to identifycorresponding pixels of an acquired first image and a succeeding orpreceding acquired second image, and generate a third image from pairsof corresponding pixels from acquired first and second images inaccordance with the teachings herein. Processor 24 transmits acquiredimages for storage and generated images for storage and display to anexternal unit (not depicted) through communication cable 52.

For use, device 68 is activated and inserted into a hollow of a subjectas known in the art, e.g., through a surgical port. Illuminator 12,image-acquirer 38 and processor 24 are activated. The distal end ofdevice 68 is directed at a surface so that light from illuminator 12passes through illumination channel 64 towards an area of interest, andis reflected. Reflected light is directed through light guide 66 toobjective 14. Objective 14 directs the light to the light sensitivesurface of image-acquirer 38, that alternately acquires a first imageand a second image depending on which LED 70 a or 70 b of illuminator 12is activated, as described above. Processor 24 receives the acquiredfirst and second images from image-acquirer 38 and generates a thirdimage from the first and second images substantially as described above.Processor 24 then transmits a generated image to be displayed on adisplay unit in real time.

Depending on the exact embodiment, devices 56 and 68 are substantiallyany suitable type of rigid endoscope including, but not limited to, alaparoscope, an anoscope, a proctoscope, a rectoscope, an otoscope, acolposcope, an arthroscope, a thoracoscope. a sigmoidoscope, arhinoscope, a bronchoscope, a cystoscope, a gynoscope, a gastroscope, amediastinoscope, a panendoscope and a hysteroscope.

EXAMPLES Example 1

A first laboratory mouse was anesthetized. The skin covering theabdominal cavity was cut to define a loose flap, and the flap securedwith needles to a flat surface, skin side down.

Using an SD-300 spectral imaging camera (ASI, Migdal Haemek, Israel)fitted with a halogen lamp illuminator and a cross-polarizing filterset, a spectral image of a portion of the inner surface of the flap wasacquired between 400 nm and 800 nm. The acquired image is reproduced, inblack-and-white, in FIG. 1A. In FIG. 1B, the spectrum of a portion ofthe image where a blood vessel was present (portion a) and the spectrumof the image where no blood vessel was present (portion b) aredisplayed.

Example 2

A second laboratory mouse was anesthetized . The skin covering theabdominal cavity was cut to define a loose flap, and the flap securedwith needles to a flat surface, skin side down.

Using an SD-300 spectral imaging camera (ASI, Migdal Haemek, Israel)fitted with a halogen lamp illuminator and a cross-polarizing filterset, a spectral image of a portion of the inner surface of the flap wasacquired between 400 nm and 800 nm.

An RGB image including all the image data acquired between 400 nm and800 nm is reproduced in black-and -white in FIG. 2A.

A red-free narrow band (520 nm-580 nm) monochrome image using dataacquired between is reproduced in black-and-white in FIG. 2B. Althoughthe contrast is superior to the equivalent RGB image, the spatialresolution appears to be similar.

An image generated in accordance with an embodiment of the methoddescribed herein where the first wavelength range was 400 nm to 600 nmand the second wavelength range was 600 nm to 800 nm, and themathematical formula describing the calculation of a pixel of thegenerated third image from the two corresponding pixels of the first andsecond images is: P3(i)=[P1(i)/P2(i)]. It is seen that the c ontrast andthe spatial resolution of the generated image is significantly betterthan of both the RGB and the red-free image.

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the scope of the appendedclaims.

For example, in some embodiments, any of the imaging assembliesdescribed herein, such as the specific imaging assemblies described indetail with reference to a specific embodiments of the device: funduscamera 10, ingestible device 30, flexible endoscope 44, or a flexibleendoscope 56 are used in other devices. For example, in some embodimentsan imaging assembly such as described with reference to fundus camera 10is used in an ingestible device, a flexible endoscope or a rigidendoscope (laparoscope).

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination or as suitable in any other describedembodiment of the invention. Certain features described in the contextof various embodiments are not to be considered essential features ofthose embodiments, unless the embodiment is inoperative without thoseelements.

Citation or identification of any reference in this application shallnot be construed as an admission that such reference is available asprior art to the invention.

Section headings are used herein to ease understanding of thespecification and should not be construed as necessarily limiting.

1. A method of generating an image of the surface of biological tissue,comprising: a) illuminating an area of interest of the surface withlight comprising wavelengths within a first wavelength range, said firstwavelength range including predominantly light having wavelengths ofbetween about 400 nm and about 620 nm; b) acquiring a first pixelatedimage of light reflected from said area of interest of the surface atsaid first wavelength range of light; c) illuminating said area ofinterest of the surface with light comprising wavelengths within asecond wavelength range, said second wavelength range includingpredominantly light having wavelengths of between about 620 nm and about800 nm; d) acquiring a second pixelated image of light reflected fromsaid area of interest of the surface at said second wavelength range oflight; and e) generating a monochromatic third pixelated image from saidfirst image and said second image by: for each desired location i ofsaid area of interest, identifying a corresponding pixel P1(i) in saidfirst image and a corresponding pixel P2(i) in said second image; andcalculating a pixel P3(i) in said third image corresponding to saidlocation i, by dividing one of a mathematical formula of P1(i) and amathematical formula of P2(i) by the other.
 2. (canceled)
 3. The methodof claim 1, wherein: said mathematical formula of P1(i) comprises amathematical formula of the form (xP1(i)+m)^(A); said mathematicalformula of P1(i) comprises a mathematical formula of the form(yP2(i)+n)^(B); and a mathematical formula describing said calculatingis substantially a mathematical formula selected from the groupconsisting of:P3(i)=[(xP1(i)+m)^(A)/(yP2(i)+n)^(B)] andP3(i)=[(yP2(i)+n)^(B)/(xP1(i)+m)^(A)], wherein A and B are,independently, any suitable positive number except 0 and including 1;wherein x and y are, independently, any suitable number including 1; andwherein m and n are, independently, any suitable number including
 0. 4.The method of claim 1, wherein a mathematical formula describing saidcalculating is substantially a mathematical formula selected from thegroup consisting of P3(i)=[P1(i)/P2(i)] and P3(i)=[P2(i)/P1(i)]. 5.(canceled)
 6. The method of claim 1, wherein said illuminating withlight comprising wavelengths within said first wavelength range issimultaneous with said illuminating with light comprising wavelengthswithin said second wavelength range.
 7. The method of claim 6, whereinsaid illuminating is with white light.
 8. The method of claim 6, whereinsaid illuminating is with light having at least two discrete wavelengthsof light: at least one discrete wavelength within said first wavelengthrange and at least one discrete wavelength within said second wavelengthrange.
 9. The method of claim 1, wherein: said acquiring of said firstpixelated image is not simultaneous with said acquiring of said secondpixelated image; said illuminating said area of interest with lightcomprising wavelengths within said first wavelength range is only duringsaid acquiring of said first pixelated image; and said illuminating saidarea of interest with light comprising wavelengths within said secondwavelength range is only during said acquiring of said second pixelatedimage.
 11. The method of claim 1, wherein said first pixelated image andsaid second pixelated image are acquired substantially simultaneously.12. The method of claim 11, comprising: directing light collected foracquiring said first image from said area of interest to a firstimage-acquirer to acquire said first image; and directing lightcollected for acquiring said second image from said area of interest toa second image-acquirer different from said first image-acquirer toacquire said second image.
 13. The method of claim 11, comprising:directing light collected for acquiring said first image and said secondimage from said area of interest to a single image-acquirer; separatingdata acquired by said single image-acquirer constituting said firstimage from data acquired by said single image-acquirer constituting saidsecond image.
 14. The method of claim 1, wherein said first image andsaid second image are acquired sequentially. 15-17. (canceled)
 18. Adevice useful for generating an image of the surface of biologicaltissue, comprising: a) an illuminator configured to illuminate an areaof interest with light comprising wavelengths within a first wavelengthrange, said first wavelength range including predominantly light havingwavelengths of between about 400 nm and about 620 nm, and to illuminatesaid area of interest with light comprising wavelengths within a secondwavelength range, said second wavelength range including predominantlylight having wavelengths of between about 620 nm and about 800 nm; b) animage-acquirer suitable for acquiring a first pixelated image of lightreflected from said area of interest of the surface of biological tissuewith said first wavelength range of light; c) an image-acquirer suitablefor acquiring a second pixelated image of light reflected from said areaof interest with said second wavelength range of light; and d) aprocessor configured to generate a monochromatic third pixelated imagefrom said first image and said second image by: for each desiredlocation i of a said area of interest, identifying a corresponding pixelP1(i) in said first image and a corresponding pixel P2(i) in said secondimage; and calculating a pixel P3(i) in said third image correspondingto said location i, by dividing one of a mathematical formula of P1(i)and a mathematical formula of P2(i) by the other.
 19. The device ofclaim 18, wherein said device is configured to acquire said first imageand said second image substantially simultaneously.
 20. The device ofclaim 18, wherein said device is configured to acquire said first imageand said second image sequentially.
 21. The device of claim 18, whereinsaid image-acquirer suitable for acquiring said first pixelated imageand said image-acquirer suitable for acquiring said second pixelatedimage are the same image-acquirer.
 22. The device of claim 18, whereinsaid image-acquirer suitable for acquiring said first pixelated imageand said image-acquirer suitable for acquiring said second pixelatedimage are different image-acquirers.
 23. The device of claim 18, furthercomprising a display component configured to visually display a saidgenerated third image. 24-25. (canceled)
 26. The device of claim 18,wherein said illuminator is configured to simultaneously illuminate saidarea of interest with light comprising wavelengths within said firstwavelength range and wavelengths within said second wavelength range.27. (canceled)
 28. The device of claim 26, wherein said illuminatorincludes at least two discrete light sources of at least two discretewavelengths of light, at least one discrete wavelength of light withinsaid first wavelength range and at least one discrete wavelength oflight within said second wavelength range.
 29. The device of claim 18,wherein said illuminator includes a source of at least two discretewavelengths of light, at least one discrete wavelength of light withinsaid first wavelength range and at least one discrete wavelength oflight within said second wavelength range, the device configured: toilluminate said area of interest with said discrete wavelength of lightwithin said first wavelength range only during acquisition of a saidfirst pixelated image; and to illuminate said area of interest with saiddiscrete wavelength of light within said second wavelength range onlyduring acquisition of a said second pixelated image.
 30. (canceled)